Bibliographic details of the publications referred to by author in this specification are collected at the end of the description. Nucleotide and amino acid sequences are referred to by a sequence identifier, i.e. (SEQ ID NO: 1), (SEQ ID NO:2), etc. A sequence listing is provided after the claims.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other country.
The designation of nucleotide residues referred to herein are those recommended by the IUPAC-IUB Biochemical Nomenclature Commission, wherein A represents Adenine, C represents Cytosine, G represents Guanine, T represents thymine, Y represents a pyrimidine residue, R represents a purine residue, M represents Adenine or Cytosine, K represents Guanine or Thymine, S represents Guanine or Cytosine, W represents Adenine or Thymine, H represents a nucleotide other than Guanine, B represents a nucleotide other than Adenine, V represents a nucleotide other than Thymine, D represents a nucleotide other than Cytosine and N represents any nucleotide residue.
The regulation of bone metabolism is a multifaceted process requiring the tight control of bone resorption and bone formation. The latter is the primary function of osteoblasts whereas bone resorption involves osteoclasts.
Osteoclasts are multinucleate cells formed in bone marrow by the fusion of cells from the monocyte/macrophage lineage (Suda et al., 1992; Quinn et al., 1998). A variety of factors play a role in regulating osteoclast formation including growth factors, systemic hormones and cell contact with marrow stroma.
A number of proteins have been identified which are involved in the process of osteoclastogenesis. Osteoprotegerin, also known as osteoclastogenesis inhibitory factor (OPG and OCIF, respectively), is a secreted member of the TNF receptor superfamily that blocks osteoclast differentiation both in vitro and in vivo (Yasuda, et al., 1998; Simonet et al., 1997). The cloning of a membrane bound ligand for OPG (OPG-ligand [OPGL]) resulted in the identification of an essential signal for proliferation and fusion of osteoclast progenitors (Yasuda, et al., 1998). This protein, also called osteoclast differentiation factor (ODF), is expressed on the plasma membrane of osteoblasts/marrow stromal cells and has a membrane bound receptor (in contrast to the soluble receptor, OPG/OCIF) identified as receptor activator of NF-kappa β (RANK). OPGL/ODF has also been termed TNF-related activation-induced cytokine (TRANCE) and RANK-ligand (RANKL). The combination of M-CSF and a soluble form of recombinant ODF, lacking the transmembrane domain, is necessary and sufficient to stimulate osteoclast generation, in the absence of osteoblast or stromal cells, from either murine spleen cells or human monocytes (Matsuzaki et al., 1998; Quinn et al., 1988).
Leptin, a cytokine produced primarily by mature adipocytes, is linked to food intake and energy expenditure (Friedman and Halaas, 1998) but also has activity in neuroendocrine, metabolic, reproductive and haemopoetic pathways (Auwerz and Staels, 1998).
In work leading up to the present invention, the inventors investigated the role of leptin in the bone microenvironment. The inventors have now identified leptin as a regulator of osteoclastogenesis. This provides the basis for the development of a range of medicaments for modulating bone resorption.